Hindawi Publishing Corporation
Research Letters in Organic Chemistry
Volume 2009 (2009), Article ID 109717
doi:10.1155/2009/109717

Research Letter

Solvent-Free Microwave Synthesis of Aryloxypropanolamines by Ring Opening of Aryloxy Epoxides

Rukhsana I. Kureshy,¹ Irshad Ahmad,² Kavita Pathak,¹ N. H. Khan,¹ Sayed H. R. Abdi,¹ H. C. Bajaj,¹ and Eringathodi Suresh³

¹Discipline of Inorganic Materials and Catalysis, Central Salt and Marine Chemicals Research Institute, Council of Scientific and Industrial Research (CSIR), G. B. Marg, Bhavnagar 364 002, Gujarat, India
²Leibniz-Institute for Surface Modification e.V. (IOM), Permoserstraße 15, 04318 Leipzig, Germany
³Analytical Science Division, Central Salt and Marine Chemicals Research Institute (CSMCRI), Bhavnagar 364 002, Gujarat, India

Correspondence should be addressed to Rukhsana I. Kureshy, rukhsana93@yahoo.co.in

Received 18 December 2008; Accepted 26 January 2009

Recommended by Kazuaki Ishihara

The ring opening reaction of aryloxyepoxides with isopropylamine under solvent-free microwave irradiation produced therapeutically useful -blockers-aryloxypropanolamines in excellent yield (up to 98%) in 10 minutes which is considerably less than the time taken in classical heating ( hours).

Copyright © 2009 Rukhsana I. Kureshy et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Introduction

Aryloxypropanolamines are important class of β-adrenergic blocking agents (β-blockers) and extensively used in medicinal chemistry for the treatment of hypertension, angina pectoris, glaucoma, anxiety, and obesity [1, 2]. The oxirane ring [3] due to its inherent polarity and strain is susceptible to the attack of nucleophiles to give propan-2-ol 3 (Scheme 1), which is known for their β-adrenoceptor antagonist activity. One of the most straightforward synthetic approaches for the preparation of β–blockers involves the heating of epoxides with an excess of amines at elevated temperature [4–7]. In recent years, various metal salts as catalysts have been reported for epoxide ring opening reaction with amine and amine derivatives giving good-to-poor regioselectivity [8–12].

Scheme 1: Solvent-free microwave-assisted ring opening of aryloxyepoxides with isopropylamine.

Microwave-assisted organic synthesis is currently gaining ground in synthetic chemistry largely due to the dramatic reduction in reaction time (from days or hours to minutes or even seconds) and advancement in the need-based design of microwave reactors [13, 14]. As a part of our ongoing research in ring opening of epoxides with amines [15–19], herein we report solvent-free microwave-assisted synthesis of aryloxypropanolamines by ring opening of aryloxyepoxides with isopropylamine. Excellent yields (up to 98%) of aryloxypropanolamines were achieved in shorter time (10 minutes) with substantially reduced quantity of amine as compared to method used under classical thermal conditions [20]. Quanitiative yields of 2-aminoalcohols have been reported earlier in the ring opening of epoxides with aliphatic and aromatic amines using montmorillonite K-10, metal salts and metal salts supported on montmorillonite K-10 as catalyst [21–23].

2. Results and Discussion

The ring opening of 3-(1-naphthoxy)-1,2-epoxy propane 1a with isopropylamine 2 in solvent-free condition was used as a representative reaction to see the effect of strength of microwave wattage and duration of its exposure on % yield of aryloxypropanolamine. Data from Table 1 shows that with an increase in microwave output power as well as reaction time, there is an increase in the formation of the product (Table 1, entries 2–9). Best result (yield, 98%) was achieved in 10 minutes at 400 W of microwave output (Table 1, entry 9) at 50°C temperature hence these conditions were used for our rest of experiments with different aryloxyepoxides 1a–f to give excellent yield (up to 98%) in 10 minutes (Figure 1). Main advantage of the present microwave-assisted epoxide ring opening protocol lies in substantial decrease in the quantity of isopropylamine (1.5 equivalent) as compared to the classical approach where the amine was used in large excess (10–15 equivalents at rt to reflux temperature) with longer duration of reaction time 4-5 hours.

Table 1: Ring opening of 3-(1-naphthoxy)-1,2-epoxy propane 1a with isopropylamine 2 under different conditions (3-(1-naphthoxy)-1,2-epoxypropane (1.0 g, 5 mmol) and isopropylamine (0.59 g, 7.5 mmol) were heated at 50°C in a Teflon reactor for the given time under specified MW power).

Entry
Conditions
Yield (a) (%)

1 (b)
Without MW
90

2
2 min/100 W
45

3
2 min/300 W
56

4
2 min/400 W
64

5
5 min/100 W
69

6
5 min/400 W
75

7
10 min/100 W
67

8
10 min/300 W
85

9
10 min/400 W
98

(a)Isolated yield after chromatographic separation.
(b)Reaction carried out for 16 hours.

Figure 1: Ring opening of aryloxyepoxides 1a–f with isopropylamine 2 under MW irradiation.

The regioselectivity of the product aryloxypropanolamines was confirmed by NMR analysis of the crude product. Single crystals X-ray analysis of representative products 3c, 3d, and 3f (Figure 1, entries 3, 4, 6) further confirmed that the desired regioisomers (Figure 2) were obtained under our microwave-assisted solvent-free epoxide ring opening reaction procedure.

Figure 2: ORTEP diagram (50% probability factor for the thermal ellipsoids) of compounds with atom numbering scheme.

3. Experimental

¹H and ¹³C NMR spectra were recorded on Bruker F113V. FTIR spectra were recorded on Perkin Elmer Spectrum GX spectrophotometer in KBr window. Microanalysis was done on a Perkin Elmer model 2400 CHNS analyzer. High-resolution mass spectra were obtained with an LC-MS (Q-TOF) LC (Waters), MS (Micromass) instruments. For the product purification, flash chromatography was performed using silica gel 60–200 mesh. ETHOS 1600 Advanced Microwave Lab station was used to conduct experiment under microwave irradiation. CCDC-612074 to-612077 contains the supplementary crystallographic data in CIF format for all the three compounds 3c, 3d, and 3f. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/datarequest/cif/.

The aryloxyepoxides were synthesized by the modified reported procedure [3d]  given as supplementary materials.

3.1. Procedure for the Preparation of Aryloxypropanolamines by Ring Opening of Aryloxy Epoxides under Solvent-Free MW Irradiation

Aryloxyepoxides 1a–f (5 mmol) and isopropylamine 2 (7.5 mmol) were taken in a closed Teflon reactor. The reactor was placed in a microwave oven at a selected power (400 W) for 10 minutes. After cooling the reactor to room temperature, excess amine was removed by distillation under reduced pressure. The purification of the reaction products was carried out by flash chromatography on silica gel using CH₂Cl₂:MeOH (95:5), dried over anhydrous Na₂SO₄. All products 3a–f were characterized by ¹H and ¹³C NMR spectroscopy and data is given as follows.

3.1.1. 1-[(1-Methylethyl) Amino]-3-(1-Naphthoxy)-2-Propanol (propranolol) (3a)

White Solid
Yield 1.27 g (98%); mp: 95–97°C; IR (KBr): ν  =  765 (CH wagging, NH bending), 1029 (CN streching), 1582 (aromatic CC stretching), 2835 (CH stretch), 3271 (OH stretch) cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ 8.22–8.27 (m, 1H, 8-CH), 7.75–7.80 (m, 1H, 11-CH), 7.29–7.48 (m, 4H, 7, 9, 10-, and 12-CH), 6.77 (d, 1H, J  =  7.4 Hz, 6-CH), 4.07–4.18 (m, 3H, OH, and 3-CH₂), 2.75–3.0 (m, 5H, NH, 1-CH₂, 2-CH, 2′-CH), 1.07 (d, 6H, J  =  6.2 Hz, 3′-CH₃); ¹³C NMR (50 MHz, CDCl₃): δ 23.7 (2  ×  3′-CH₃), 49.7 (2′-CH), 50.4 (1-CH₂), 69.3 (2-CH), 71.6 (3-CH₂), 105.8 (6-CH), 121.3 (12-CH), 122.6 (9-CH), 126.0 (11-CH), 126.4 (10-CH), 126.6 (8-CH), 127.1 (7a-c), 128.3(11a-c), 135.3 (7-CH), (155.2 5-C); LC-MS m/z 260 [M  +  H]; analytical calculation for C₁₆H₂₁NO₂: C, 74.10; H, 8.16; N, 5.40 found C, 74.0; H, 8.10; N, 5.30.

3.1.2. 1-[4-(2-Methoxyethyl) Phenoxy]-3-[(1-Methylethyl) Amino]-2-Propanol (metoprolol) (3b)

White Solid
Yield 1.249 g (97%); mp: 96–98°C; IR (KBr): ν  =  828(CH wagging, NH bending), 1113(CN streching), 1512(aromatic CC stretching), 2869(CH stretch), 3301(OH stretching) cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ 7.07 (d, 2H, J  =  8.2 Hz, 7- and 9-CH), 6.79 (d, 2H, J  =  8.2 Hz, 6- and 10-CH), 4.14 (m, 2H, 3-CH₂), 3.90 (m, 3H, OH, NH, and 2′-CH), 3.53 (t, 2H, J   =  7.0 Hz, 8a-CH₂), 3.32 (s, 3H, 8d-CH₃), 2.79 (t, 2H, J  =  7.0 Hz, 8b-CH₂), 2.76 (m, 3H, 2-CH, 1-CH₂), 1.05 (d, 6H, J  =  6.2 Hz, 2  ×  3′-CH₃);¹³ C NMR (50 MHz, CDCl₃): δ 23.2 (2  ×  3′-CH₃), 35.6 (8a-CH₂), 49.2 (2′-CH), 50.1(1-CH₂), 58.9 (8d-CH₃), 68.7 (2-CH), 71.3 (3-CH₂), 74.2 (8b-CH₂), 114.8 (6 and 10-CH), 130.1 (7- and 9-CH), 131.7 (8-C), 157.6 (5-C); LC-MS m/z 269; analytical calculation for C₁₅H₂₅NO₃: C, 67.38; H, 9.42.; N, 5.24 found C, 67.12; H, 9.23; N, 5.12.

3.1.3. 1-[(1-Methylethyl) Amino]-3-(1-Phenoxy)-2-Propanol (3c)

White Solid
Yield 0.993 g (95%); mp: 75–78°C; IR (KBr): ν  =  802(CH wagging, NH bending), 1177(CN streching), 1513(aromatic CC stretching), 2875(CH stretch), 3308(OH stretching) cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ 7.25 (m, 2H, 7- and 9-CH), 6.91 (m, 3H, 6-, 8-, and 10-CH), 4.11 (m, 3H, 3-CH₂, and 2-CH), 3.94 (m, 1H, 2′-CH), 3.56 (bs, 1H, OH), (m, 3H, NH, 1-CH₂), 1.07 (d, 6H, J  =  6.4 Hz, 2  ×  3′-CH₃); ¹³C NMR (50 MHz, CDCl₃): δ 23.2 (2  ×  3′-CH₃), 49.5 (2′-CH), 50.1 (1-CH₂), 68.8 (2-CH), 71.2 (3-CH₂), 115.1 (6- and 10-CH), 121.5 (8-CH), 130.0 (7- and 9-CH), 159.2 (5-C); LC-MS m/z 211; analytical calculation for C₁₂H₁₉NO₂: C, 68.87; H, 9.15; N, 6.69 found C, 68.58; H, 9.00; N, 6.59.

3.1.4. 1-[(1-Methylethyl) Amino]-3-(4-Methylphenoxy)-2-Propanol (3d)

White Solid
Yield 1.048 g (94%); mp: 75–77°C; IR (KBr): ν  =  803(CH wagging, NH bending), 1177(CN streching), 1513(aromatic CC stretching), 2875(CH stretching), 3308 (OH stretching) cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ 7.07 (d, 2H, J  =  8.4 Hz, 7- and 9-CH), 6.81 (d, 2H, J  =  8.4 Hz, 6- and 10-CH), 4.08 (m, 2H, 3-CH₂), 3.92 (m, 2H, OH, and 2-CH), 3.28 (bs, 1H, NH), (m, 3H, 1-CH₂, 2- and 2′-CH), 2.27 (s, 3H, 8a-CH₃), 1.10 (d, 6H, J  =  6.2 Hz, 2  ×  3′-CH₃); ¹³C NMR (50 MHz, CDCl₃): δ 21.0 (8a-CH₃), 23.4 (2  ×  3′-CH₃), 49.5 (2′-CH), 50.1(1-CH₂), 69.0(2-CH), 71.4 (3-CH₂), 115.0 (6- and 10-CH), 130.5 (8-C), 130.7 (7- and 9-CH),157.2 (5-C); LC-MS m/z 224; analytical calculation for C₁₃H₂₁NO₂: C, 69.92; H, 9.48; N, 6.27 found C, 69.86; H, 9.38; N, 6.20.

3.1.5. 1-[(1-Methylethyl) Amino]-3-(4-Cynophenoxy)-2-Propanol (3e)

Colorless Solid
Yield 1.123 g (96%); mp: 108–110°C; IR (KBr): ν  =  839(CH wagging, NH bending), 1173(CN streching), 1508(aromatic CC stretching), 2932(CH stretching), 3504(OH stretching) cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ 7.58 (d, 2H, J  =  8.2, 7- and 9-CH), 7.01 (d, 2H, J  =  8.2 Hz, 6- and 10-CH), 4.22 (m, 2H, 3-CH₂), 4.02 (bs, 1H, OH), 3.30 (bs, 1H, NH), (m, 4H, 1-CH₂, 2- and 2′-CH), 1.08 (d, 6H, J  =  6.2 Hz, 2  ×  3′-CH₃); ¹³C NMR (50 MHz, CDCl₃): δ 23.3 (2  ×  3′-CH₃), 49.4 (2′-CH), 49.7 (1-CH₂), 68.6 (2-CH), 71.5 (3-CH₂), 104.5 (8-C), 115.8 (6- and 10-CH), 118.0 (8a-CN), 134.4 (7- and 9-CH), 162.5(5-C); LC-MS m/z 235; analytical calculation for C₁₃H₁₈N₂O₂: C, 66.64; H, 7.74; N, 11.96 found C, 66.51; H, 7.60; N, 11.88.

3.1.6. 1-[(1-Methylethyl) Amino]-3-(4-Methoxyphenoxy)-2-Propanol (3f)

Colorless Solid
Yield 1.123 g (94%); mp: 80–82°C; IR (in KBr): ν  =  830(CH wagging, NH bending), 1115(CN streching), 1525(aromatic CC stretching), 2928(CH stretching), 3301(OH stretching) cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ 6.8 (s, 4H, 6, 7, 9-, and 10-CH), 4.08 (m, 2H, OH, 3-CH₂), (m, 1H, 2-CH), 3.73 (s, 3H, 8b-CH₃), (bs, 1H, NH), (m, 4H, 1-CH₂, 2- and 2′-CH), 1.06 (d, 6H, J  =  6.2 Hz, 2  ×  3′-CH₃); ¹³C NMR (50 MHz, CDCl₃): δ 23.4 (2  ×  3′-CH₃), 49.4 (2′-CH), 50.2 (1-CH₂), 56.1 (8b-CH₃), 69.1(2-CH), 72.1(3-CH₂), 115.2 (6- and 10-CH), 116.0 (7- and 9-CH), 153.5 (5-C), 154.5 (8-C); LC-MS m/z 240 [M  +  H]⁺; analytical calculation for C₁₃H₂₁NO₃: C, 65.25; H, 8.84; N, 5.85 found C, 65.20; H, 8.69; N, 5.78.

Acknowledgments

R. I. Kureshy is thankful to DST and CSIR Net Work Project on Catalysis.

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